Inflammation driven by NF-ĸB compromises bone formation by inducing the differentiation of osteoblasts into atypical inflammatory osteocyte-like cells

Abstract

Inflammation causes bone loss by dysregulating the differentiation and functions of osteoclasts, osteoblasts, and osteocytes. This process can be modeled by the expression of constitutively activated IKK2 (IKK2ca), a strategy that we leveraged to investigate the mechanisms through which inflammation negatively affects cells of the osteoblast/osteocyte lineage. We found that mice expressing IKK2ca in osteoblasts exhibit significant bone loss. Mechanistically, IKK2ca downregulates the expression of osteoblast genes while inducing the differentiation of bone-forming osteoblasts into catabolic osteocytes like cells, expressing high levels of Podoplanin, Fgf23, Dkk1 and Sclerostin. We term these atypical inflammatory osteocyte-like cells (aiOCy-L cells) as they highly express inflammatory and senescence markers and promote osteoclast differentiation as well. Additional data show that inflammation induces abnormal differentiation of OB into aiOCy-L cells through upregulating mTOR and glycolysis. In summary, we uncovered a mechanism by which inflammation alters osteoblast differentiation and fate decision via the IKK2/mTOR/glycolysis axis.

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Funding

U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)(P30AR074992)

Pilot and Feasibility Grant, Musculoskeletal Research Center, Washington University School of Medicine (P30AR074992, P30AR057235)

U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)(AI161022)

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